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  2. saito takeo

saito takeo

  (齋藤 竹生)

Profile Information

Affiliation
School of Medicine Faculty of Medicine, Fujita Health University
Degree
医学博士(藤田医科大学)
J-GLOBAL ID
201501001954870181
researchmap Member ID
7000013117

Research Areas

 1

Research History

 3

Education

 2

Awards

 5

Papers

 55
  • Ryohei Sakai, Shu Aizawa, Hyeon-Cheol Lee-Okada, Katsunori Hase, Hiromi Fujita, Hisae Kikuchi, Yukiko U Inoue, Takayoshi Inoue, Chihana Kabuta, Takehiko Yokomizo, Tadafumi Hashimoto, Keiji Wada, Tatsuo Mano, Ikuko Koyama-Honda, Tomohiro Kabuta
    Cell reports, 44(6) 115829-115829, Jun 24, 2025  
    Lifestyle diseases, such as obesity, diabetes, and metabolic syndrome, are leading health problems, most of which are related to abnormal lipid metabolism. Lysosomes can degrade lipid droplets (LDs) via microautophagy, but the regulatory factors and physiological significance of this process are not fully understood. Here, we report the molecular mechanism and pathophysiological roles of microlipophagy, regulated by the lysosomal membrane protein LAMP2B. Our study reveals that LAMP2B interacts with phosphatidic acid, facilitating lysosomal-LD interactions and enhancing lipid hydrolysis via microlipophagy depending on endosomal sorting complexes required for transport. Correlative light and electron microscopy demonstrates direct LD uptake into lysosomes at contact sites. Moreover, LAMP2B overexpression in mice prevents high-fat diet-induced obesity, insulin resistance, and adipose tissue inflammation; liver lipidomics analysis suggests enhanced triacylglycerol hydrolysis. Overall, the findings of this study elucidate the mechanism of microlipophagy, which could be promising for the treatment of obesity and related disorders.
  • Sarah M C Colbert, Lauren Lepow, Brian Fennessy, Nakao Iwata, Masashi Ikeda, Takeo Saito, Chikashi Terao, Michael Preuss, Jyotishman Pathak, J John Mann, Hilary Coon, Niamh Mullins
    Translational psychiatry, 15(1) 63-63, Feb 20, 2025  
    Suicidal ideation (SI) and behavior (SB) are major public health concerns, but risk factors for their development and progression are poorly understood. We used ICD codes and a natural language processing algorithm to identify individuals in a hospital biobank with SI-only, SB, and controls without either. We compared the profiles of SB and SI-only patients to controls, and each other, using phenome-wide association studies (PheWAS) and polygenic risk scores (PRS). PheWAS identified many risk factors for SB and SI-only, plus specific psychiatric disorders which may be involved in progression from SI-only to SB. PRS for suicide attempt were only associated with SB, and even after accounting for psychiatric disorder PRS. SI PRS were only associated with SI-only, although not after accounting for psychiatric disorder PRS. These findings advance understanding of distinct genetic and clinical risk factors for SB and SI-only, which will aid in early detection and intervention efforts.
  • Kevin S O'Connell, Maria Koromina, Tracey van der Veen, Toni Boltz, Friederike S David, Jessica Mei Kay Yang, Keng-Han Lin, Xin Wang, Jonathan R I Coleman, Brittany L Mitchell, Caroline C McGrouther, Aaditya V Rangan, Penelope A Lind, Elise Koch, Arvid Harder, Nadine Parker, Jaroslav Bendl, Kristina Adorjan, Esben Agerbo, Diego Albani, Silvia Alemany, Ney Alliey-Rodriguez, Thomas D Als, Till F M Andlauer, Anastasia Antoniou, Helga Ask, Nicholas Bass, Michael Bauer, Eva C Beins, Tim B Bigdeli, Carsten Bøcker Pedersen, Marco P Boks, Sigrid Børte, Rosa Bosch, Murielle Brum, Ben M Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Judit Cabana-Domínguez, Murray J Cairns, Bernardo Carpiniello, Miquel Casas, Pablo Cervantes, Chris Chatzinakos, Hsi-Chung Chen, Tereza Clarence, Toni-Kim Clarke, Isabelle Claus, Brandon Coombes, Elizabeth C Corfield, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Piotr M Czerski, Konstantinos Dafnas, Anders M Dale, Nina Dalkner, Franziska Degenhardt, J Raymond DePaulo, Srdjan Djurovic, Ole Kristian Drange, Valentina Escott-Price, Ayman H Fanous, Frederike T Fellendorf, I Nicol Ferrier, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B Freimer, John F Fullard, Julie Garnham, Ian R Gizer, Scott D Gordon, Katherine Gordon-Smith, Tiffany A Greenwood, Jakob Grove, José Guzman-Parra, Tae Hyon Ha, Tim Hahn, Magnus Haraldsson, Martin Hautzinger, Alexandra Havdahl, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Ian B Hickie, Per Hoffmann, Peter A Holmans, Ming-Chyi Huang, Masashi Ikeda, Stéphane Jamain, Jessica S Johnson, Lina Jonsson, Janos L Kalman, Yoichiro Kamatani, James L Kennedy, Euitae Kim, Jaeyoung Kim, Sarah Kittel-Schneider, James A Knowles, Manolis Kogevinas, Thorsten M Kranz, Kristi Krebs, Steven A Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J MacIntyre, Wolfgang Maier, Adam X Maihofer, Dolores Malaspina, Mirko Manchia, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Nathaniel W McGregor, Melvin G McInnis, James D McKay, Helena Medeiros, Andreas Meyer-Lindenberg, Vincent Millischer, Derek W Morris, Paraskevi Moutsatsou, Thomas W Mühleisen, Claire O'Donovan, Catherine M Olsen, Georgia Panagiotaropoulou, Sergi Papiol, Antonio F Pardiñas, Hye Youn Park, Amy Perry, Andrea Pfennig, Claudia Pisanu, James B Potash, Digby Quested, Mark H Rapaport, Eline J Regeer, John P Rice, Margarita Rivera, Eva C Schulte, Fanny Senner, Alexey Shadrin, Paul D Shilling, Engilbert Sigurdsson, Lisa Sindermann, Lea Sirignano, Dan Siskind, Claire Slaney, Laura G Sloofman, Olav B Smeland, Daniel J Smith, Janet L Sobell, Maria Soler Artigas, Dan J Stein, Frederike Stein, Mei-Hsin Su, Heejong Sung, Beata Świątkowska, Chikashi Terao, Markos Tesfaye, Martin Tesli, Thorgeir E Thorgeirsson, Jackson G Thorp, Claudio Toma, Leonardo Tondo, Paul A Tooney, Shih-Jen Tsai, Evangelia Eirini Tsermpini, Marquis P Vawter, Helmut Vedder, Annabel Vreeker, James T R Walters, Bendik S Winsvold, Stephanie H Witt, Hong-Hee Won, Robert Ye, Allan H Young, Peter P Zandi, Lea Zillich, Rolf Adolfsson, Martin Alda, Lars Alfredsson, Lena Backlund, Bernhard T Baune, Frank Bellivier, Susanne Bengesser, Wade H Berrettini, Joanna M Biernacka, Michael Boehnke, Anders D Børglum, Gerome Breen, Vaughan J Carr, Stanley Catts, Sven Cichon, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M Fullerton, Micha Gawlik, Elliot S Gershon, Fernando S Goes, Melissa J Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans A Henskens, Jens Hjerling-Leffler, David M Hougaard, Kristian Hveem, Nakao Iwata, Ian Jones, Lisa A Jones, René S Kahn, John R Kelsoe, Tilo Kircher, George Kirov, Po-Hsiu Kuo, Mikael Landén, Marion Leboyer, Qingqin S Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Jurjen J Luykx, Nicholas G Martin, Carol A Mathews, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Sarah E Medland, Ingrid Melle, Lili Milani, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bertram Müller-Myhsok, Richard M Myers, Woojae Myung, Benjamin M Neale, Caroline M Nievergelt, Merete Nordentoft, Markus M Nöthen, John I Nurnberger, Michael C O'Donovan, Ketil J Oedegaard, Tomas Olsson, Michael J Owen, Sara A Paciga, Christos Pantelis, Carlos N Pato, Michele T Pato, George P Patrinos, Joanna M Pawlak, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A Rouleau, Panos Roussos, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R Schofield, Thomas G Schulze, Laura J Scott, Rodney J Scott, Alessandro Serretti, Jordan W Smoller, Alessio Squassina, Eli A Stahl, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Irwin D Waldman, Cynthia S Weickert, Thomas W Weickert, Thomas Werge, David C Whiteman, John-Anker Zwart, Howard J Edenberg, Andrew McQuillin, Andreas J Forstner, Niamh Mullins, Arianna Di Florio, Roel A Ophoff, Ole A Andreassen
    Nature, 639(8056) 968-975, Jan 22, 2025  
    Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.
  • Hyeon-Cheol Lee-Okada, Chengxuan Xue, Takehiko Yokomizo
    Biochimica et biophysica acta. Molecular and cell biology of lipids, 1870(1) 159564-159564, Jan, 2025  
    Polyunsaturated fatty acids (PUFAs)-fatty acids containing multiple double bonds within their carbon chain-are an indispensable component of the cell membrane. PUFAs, including the omega-6 PUFA arachidonic acid (ARA; C20:4n-6) and the omega-3 PUFAs eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3), have been implicated in various (patho)physiological events. These PUFAs are either obtained from the diet or biosynthesized from the essential fatty acids linoleic acid (LA; C18:2n-6) and α-linolenic acid (ALA; C18:3n-3) via enzymatic reactions that are catalyzed by fatty acid elongases (ELOVL2 and ELOVL5) and fatty acid desaturases (FADS1 and FADS2). In this review, we summarize the recent literature studying the role of PUFAs, placing a special emphasis on the newly discovered functions of PUFAs and their biosynthetic pathway as revealed by studies using animal models targeting the PUFA biosynthetic pathway and genetic approaches including genome-wide association studies.
  • Masahiro Nakatochi, Itaru Kushima, Branko Aleksic, Hiroki Kimura, Hidekazu Kato, Toshiya Inada, Youta Torii, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Shuji Iritani, Nakao Iwata, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Tsutomu Takahashi, Michio Suzuki, Takahiro A Kato, Shigenobu Kanba, Hideki Horikawa, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Tadafumi Kato, Chihiro Kakiuchi, Bun Yamagata, Shintaro Nio, Yasuto Kunii, Hirooki Yabe, Yasunobu Okamura, Shu Tadaka, Ueno Fumihiko, Taku Obara, Yasuyuki Yamamoto, Yuko Arioka, Daisuke Mori, Masashi Ikeda, Norio Ozaki
    Psychiatry and clinical neurosciences, 79(1) 12-20, Jan, 2025  
    AIM: Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. METHODS: Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. RESULTS: The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). CONCLUSION: We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.
  • Takuma Ashizawa, Takeo Saito, Tomo Okochi, Kohei Ninomiya, Kenta Ito, Rei Aoki, Masashi Ikeda, Nakao Iwata
    Translational Psychiatry, 14(1), Oct 14, 2024  
    Abstract Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.36, p = 0.023) and arachidonic acid (AA) (β = −0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.
  • Satoshi Koyama, Xiaoxi Liu, Yoshinao Koike, Keiko Hikino, Masaru Koido, Wei Li, Kotaro Akaki, Kohei Tomizuka, Shuji Ito, Nao Otomo, Hiroyuki Suetsugu, Soichiro Yoshino, Masato Akiyama, Kohei Saito, Yuki Ishikawa, Christian Benner, Pradeep Natarajan, Patrick T Ellinor, Taisei Mushiroda, Momoko Horikoshi, Masashi Ikeda, Nakao Iwata, Koichi Matsuda, Shumpei Niida, Kouichi Ozaki, Yukihide Momozawa, Shiro Ikegawa, Osamu Takeuchi, Kaoru Ito, Chikashi Terao
    Nature genetics, 56(10) 2027-2035, Oct, 2024  
    Human genetic variants are associated with many traits through largely unknown mechanisms. Here, combining approximately 260,000 Japanese study participants, a Japanese-specific genotype reference panel and statistical fine-mapping, we identified 4,423 significant loci across 63 quantitative traits, among which 601 were new, and 9,406 putatively causal variants. New associations included Japanese-specific coding, splicing and noncoding variants, exemplified by a damaging missense variant rs730881101 in TNNT2 associated with lower heart function and increased risk for heart failure (P = 1.4 × 10-15 and odds ratio = 4.5, 95% confidence interval = 3.1-6.5). Putative causal noncoding variants were supported by state-of-art in silico functional assays and had comparable effect sizes to coding variants. A plausible example of new mechanisms of causal variants is an enrichment of causal variants in 3' untranslated regions (UTRs), including the Japanese-specific rs13306436 in IL6 associated with pro-inflammatory traits and protection against tuberculosis. We experimentally showed that transcripts with rs13306436 are resistant to mRNA degradation by regnase-1, an RNA-binding protein. Our study provides a list of fine-mapped causal variants to be tested for functionality and underscores the importance of sequencing, genotyping and association efforts in diverse populations.
  • Masakazu Hatano, Haruna Araki, Takeo Saito, Shigeki Yamada
    Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 22(3) 442-450, Aug 31, 2024  
    OBJECTIVE: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). RESULTS: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. CONCLUSION: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation.
  • Lucia Trastulla, Georgii Dolgalev, Sylvain Moser, Laura T Jiménez-Barrón, Till F M Andlauer, Moritz von Scheidt, Monika Budde, Urs Heilbronner, Sergi Papiol, Alexander Teumer, Georg Homuth, Henry Völzke, Marcus Dörr, Peter Falkai, Thomas G Schulze, Julien Gagneur, Francesco Iorio, Bertram Müller-Myhsok, Heribert Schunkert, Michael J Ziller
    Nature communications, 15(1) 5534-5534, Jul 1, 2024  
    Stratified medicine holds great promise to tailor treatment to the needs of individual patients. While genetics holds great potential to aid patient stratification, it remains a major challenge to operationalize complex genetic risk factor profiles to deconstruct clinical heterogeneity. Contemporary approaches to this problem rely on polygenic risk scores (PRS), which provide only limited clinical utility and lack a clear biological foundation. To overcome these limitations, we develop the CASTom-iGEx approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue specific gene expression levels. The paradigmatic application of this approach to coronary artery disease or schizophrenia patient cohorts identified diverse strata or biotypes. These biotypes are characterized by distinct endophenotype profiles as well as clinical parameters and are fundamentally distinct from PRS based groupings. In stark contrast to the latter, the CASTom-iGEx strategy discovers biologically meaningful and clinically actionable patient subgroups, where complex genetic liabilities are not randomly distributed across individuals but rather converge onto distinct disease relevant biological processes. These results support the notion of different patient biotypes characterized by partially distinct pathomechanisms. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine paradigms.
  • Eduardo A Maury, Maxwell A Sherman, Giulio Genovese, Thomas G Gilgenast, Tushar Kamath, S J Burris, Prashanth Rajarajan, Erin Flaherty, Schahram Akbarian, Andrew Chess, Steven A McCarroll, Po-Ru Loh, Jennifer E Phillips-Cremins, Kristen J Brennand, Evan Z Macosko, James T R Walters, Michael O'Donovan, Patrick Sullivan, Jonathan Sebat, Eunjung A Lee, Christopher A Walsh
    Cell genomics, 3(8) 100356-100356, Aug 9, 2023  
    While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)-present in some but not all cells-remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e-4), with recurrent somatic deletions of exons 1-5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5' deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk.
  • Hirona Yamamoto, Hyeon-Cheol Lee-Okada, Masashi Ikeda, Takumi Nakamura, Takeo Saito, Atsushi Takata, Takehiko Yokomizo, Nakao Iwata, Tadafumi Kato, Takaoki Kasahara
    Molecular Psychiatry, 28(7) 2848-2856, Feb 21, 2023  Peer-reviewed
    Abstract Large-scale genome-wide association studies (GWASs) on bipolar disorder (BD) have implicated the involvement of the fatty acid desaturase (FADS) locus. These enzymes (FADS1 and FADS2) are involved in the metabolism of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are thought to potentially benefit patients with mood disorders. To model reductions in the activity of FADS1/2 affected by the susceptibility alleles, we generated mutant mice heterozygously lacking both Fads1/2 genes. We measured wheel-running activity over six months and observed bipolar swings in activity, including hyperactivity and hypoactivity. The hyperactivity episodes, in which activity was far above the norm, usually lasted half a day; mice manifested significantly shorter immobility times on the behavioral despair test performed during these episodes. The hypoactivity episodes, which lasted for several weeks, were accompanied by abnormal circadian rhythms and a marked decrease in wheel running, a spontaneous behavior associated with motivation and reward systems. We comprehensively examined lipid composition in the brain and found that levels of certain lipids were significantly altered between wild-type and the heterozygous mutant mice, but no changes were consistent with both sexes and either DHA or EPA was not altered. However, supplementation with DHA or a mixture of DHA and EPA prevented these episodic behavioral changes. Here we propose that heterozygous Fads1/2 knockout mice are a model of BD with robust constitutive, face, and predictive validity, as administration of the mood stabilizer lithium was also effective. This GWAS-based model helps to clarify how lipids and their metabolisms are involved in the pathogenesis and treatment of BD.
  • Masakazu Hatano, Kaho Yamada, Haruna Matsuzaki, Rina Yokoi, Takeo Saito, Shigeki Yamada
    PloS one, 18(6) e0287122, 2023  
    Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.
  • Haruna Matsuzaki, Masakazu Hatano, Miko Iwata, Takeo Saito, Shigeki Yamada
    Neuropsychiatric disease and treatment, 19 615-622, 2023  
    PURPOSE: Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. PATIENTS AND METHODS: This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. RESULTS: We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. CONCLUSION: The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.
  • Masashi Ikeda, Takeo Saito, Tetsufumi Kanazawa, Taro Kishi, Nakao Iwata
    Psychiatry and clinical neurosciences, 76(11) 596-598, Nov, 2022  
  • Takeo Saito, Masashi Ikeda, Chikashi Terao, Takuma Ashizawa, Masami Miyata, Satoshi Tanaka, Tetsufumi Kanazawa, Tadafumi Kato, Taro Kishi, Nakao Iwata
    Psychiatry and clinical neurosciences, 77(2) 118-119, Oct 25, 2022  
  • Itaru Kushima, Masahiro Nakatochi, Branko Aleksic, Takashi Okada, Hiroki Kimura, Hidekazu Kato, Mako Morikawa, Toshiya Inada, Kanako Ishizuka, Youta Torii, Yukako Nakamura, Satoshi Tanaka, Miho Imaeda, Nagahide Takahashi, Maeri Yamamoto, Kunihiro Iwamoto, Yoshihiro Nawa, Nanayo Ogawa, Shuji Iritani, Yu Hayashi, Tzuyao Lo, Gantsooj Otgonbayar, Sho Furuta, Nakao Iwata, Masashi Ikeda, Takeo Saito, Kohei Ninomiya, Tomo Okochi, Ryota Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenichiro Miura, Masanari Itokawa, Makoto Arai, Mitsuhiro Miyashita, Kazuya Toriumi, Kazutaka Ohi, Toshiki Shioiri, Kiyoyuki Kitaichi, Toshiyuki Someya, Yuichiro Watanabe, Jun Egawa, Tsutomu Takahashi, Michio Suzuki, Tsukasa Sasaki, Mamoru Tochigi, Fumichika Nishimura, Hidenori Yamasue, Hitoshi Kuwabara, Tomoyasu Wakuda, Takahiro A Kato, Shigenobu Kanba, Hideki Horikawa, Masahide Usami, Masaki Kodaira, Kyota Watanabe, Takeo Yoshikawa, Tomoko Toyota, Shigeru Yokoyama, Toshio Munesue, Ryo Kimura, Yasuko Funabiki, Hirotaka Kosaka, Minyoung Jung, Kiyoto Kasai, Tempei Ikegame, Seiichiro Jinde, Shusuke Numata, Makoto Kinoshita, Tadafumi Kato, Chihiro Kakiuchi, Kazuhiro Yamakawa, Toshimitsu Suzuki, Naoki Hashimoto, Shuhei Ishikawa, Bun Yamagata, Shintaro Nio, Toshiya Murai, Shuraku Son, Yasuto Kunii, Hirooki Yabe, Masumi Inagaki, Yu-Ichi Goto, Yuto Okumura, Tomoya Ito, Yuko Arioka, Daisuke Mori, Norio Ozaki
    Biological psychiatry, 92(5) 362-374, Sep 1, 2022  
    BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.
  • Takeo Saito, Toru Usui, Hiroshi Inada, Izuru Miyawaki, Kentaro Mizuno, Masashi Ikeda, Nakao Iwata
    Journal of psychopharmacology (Oxford, England), 36(9) 2698811221112937-2698811221112937, Jul 21, 2022  
    BACKGROUND: Although clozapine-induced granulocytopenia (CIG) is less severe than clozapine-induced agranulocytosis (CIA), and some patients with CIG may not go on to develop serious complications, clozapine is discontinued in cases of both CIA and CIG. Understanding the pathogenic mechanisms of CIA/CIG could provide better management of clozapine therapy. Recently, as a mechanistic insight into adaptive immune systems, European groups reported clozapine-specific proliferative responses and clozapine-specific T cells using blood taken from patients with CIA and/or CIG. AIMS: The aims of our study are to support this mechanistic evidence and to investigate the difference in the lymphocyte response to clozapine between patients with CIG and those with CIA. METHODS: Lymphocyte stimulation tests (LSTs) were conducted using CD25-positive cell-depleted peripheral blood-derived mononuclear cells (PBMCs) isolated from blood of four Japanese patients with CIA, four patients with CIG, and nine clozapine-tolerant subjects. RESULTS: Three of four patients with CIA and one of four patients with CIG showed proliferative responses to clozapine with a stimulation index of greater than 2. In contrast, none of the nine clozapine-tolerant subjects showed any response to clozapine. Olanzapine did not stimulate PBMCs of patients with CIA, patients with CIG, or clozapine-tolerant subjects. CONCLUSIONS: Clozapine- and CIA-specific lymphocyte reactions in a Japanese population provided supportive evidence that the pathogenesis of CIA is based on adaptive immune reactions. In addition, patients with CIG who show a positive response to an LST may at the very least not be chosen for clozapine-rechallenge and further prospective studies are desirable to verify this hypothesis.
  • Rei Aoki, Takeo Saito, Kohei Ninomiya, Ayu Shimasaki, Takuma Ashizawa, Kenta Ito, Masashi Ikeda, Nakao Iwata
    Psychiatry and clinical neurosciences, 76(8) 361-366, May 10, 2022  
    AIM: The genetic relationship between schizophrenia (SCZ) and other nonpsychiatric disorders remains largely unknown. We examined the shared genetic components between these disorders based on multipopulation data sets. METHODS: We used two data sets for East Asian (EAS) and European (EUR) samples. SCZ data was based on the Psychiatric Genomics Consortium Asia with our own genome-wide association study for EAS and Psychiatric Genomics Consortium for EUR. Nonpsychiatric data (20 binary traits [mainly nonpsychiatric complex disorders] and 34 quantitative traits [mainly laboratory examinations and physical characteristics]) were obtained from Biobank Japan and UK Biobank for EAS and EUR samples, respectively. To evaluate genetic correlation, linkage disequilibrium score regression analysis was utilized with further meta-analysis for each result from EAS and EUR samples to obtain robust evidence. Subsequent mendelian randomization analysis was also included to examine the causal effect. RESULTS: A significant genetic correlation between SCZ and several metabolic syndrome (MetS) traits was detected in the combined samples (meta-analysis between EAS and EUR data) (body mass index [rg  = -0.10, q-value = 1.0 × 10-9 ], high-density-lipoprotein cholesterol [rg  = 0.072, q-value = 2.9 × 10-3 ], blood sugar [rg  = -0.068, q-value = 1.4 × 10-2 ], triglycerides [rg  = -0.052, q-value = 2.4 × 10-2 ], systolic blood pressure [rg  = -0.054, q-value = 3.5 × 10-2 ], and C-reactive protein [rg  = -0.076, q-value = 7.8 × 10-5 ]. However, no causal relationship on SCZ susceptibility was detected for these traits based on the mendelian randomization analysis. CONCLUSION: Our results indicate shared genetic components between SCZ and MetS traits and C-reactive protein. Specifically, we found it interesting that the correlation between MetS traits and SCZ was the opposite of that expected from clinical studies: this genetic study suggests that SCZ susceptibility was associated with reduced MetS. This implied that MetS in patients with SCZ was not associated with genetic components but with environmental factors, including antipsychotics, lifestyle changes, poor diet, lack of exercise, and living conditions.
  • Ryo Morikawa, Yuichiro Watanabe, Hirofumi Igeta, Reza K Arta, Masashi Ikeda, Satoshi Okazaki, Satoshi Hoya, Takeo Saito, Ikuo Otsuka, Jun Egawa, Takaki Tanifuji, Nakao Iwata, Toshiyuki Someya
    Psychiatry research, 310 114481-114481, Apr, 2022  
    SETD1A has been identified as a substantial risk gene for schizophrenia. To further investigate the role of SETD1A in the genetic etiology of schizophrenia in the Japanese population, we performed resequencing and association analyses. First, we resequenced the SETD1A coding regions of 974 patients with schizophrenia. Then, we genotyped variants, prioritized via resequencing, in 2,027 patients with schizophrenia and 2,664 controls. Next, we examined the association between SETD1A and schizophrenia in 3,001 patients with schizophrenia and 2,664 controls. Finally, we performed a retrospective chart review of patients with prioritized SETD1A variants. We identified two novel missense variants (p.Ser575Pro and p.Glu857Gln) via resequencing. We did not detect these variants in 4,691 individuals via genotyping. These variants were not significantly associated with schizophrenia in the association analysis. Additionally, we found that a schizophrenia patient with the p.Glu857Gln variant had developmental delays. In conclusion, novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia. However, our study does not provide evidence for the contribution of these variants to the genetic etiology of schizophrenia in the Japanese population.
  • Kohei Ninomiya, Takeo Saito, Masashi Ikeda, Nakao Iwata, François R Girardin
    Frontiers in pharmacology, 13 1016669-1016669, 2022  
    The identification of pharmacogenetic factors that increase the susceptibility to clozapine-induced agranulocytosis or granulocytopenia (CIAG) has received increasing interest. The SLCO1B3-SCLO1B7 variant (rs149104283) and single amino acid changes in human leukocyte antigen (HLA) HLA-DQB1 (126Q) and HLA-B (158T) were associated with an increased risk of CIAG. In this study, we evaluated the effectiveness and cost-effectiveness of adding the SLCO1B3-SCLO1B7 to HLA variants as a new pharmacogenomic (PGx) approach and explored the evolution of a cohort of schizophrenic patients taking long-term clozapine as a third-line antipsychotic medication. The decision model included probabilistic and deterministic sensitivity analyses to assess the expected costs and quality-adjusted life-years (QALYs). The current monitoring scheme was compared with the PGx-guided strategy, where all patients underwent pre-emptively a genetic test before taking clozapine, over 10 years. By adding the SLCO1B3-SCLO1B7 variant into HLA variants, CIAG sensitivity increased from 36.0% to 43.0%, the specificity decreased from 89.0% to 86.9%, and the probability of cost-effectiveness improved from 74.1% to 87.8%. The incremental cost-effectiveness ratio was £16,215 per QALY and remained below the conventional decision threshold (£30,000 or US$50,000 per QALY). Therefore, the SLCO1B3-SCLO1B7 variant, as an additional risk allele to HLA variants, increases preemptive test sensitivity and improves the effectiveness and cost-effectiveness of PGx-guided clozapine administration.
  • Kohei Ninomiya, Takeo Saito, Tomo Okochi, Satoru Taniguchi, Ayu Shimasaki, Rei Aoki, Takeo Hata, Taisei Mushiroda, Tetsufumi Kanazawa, Masashi Ikeda, Nakao Iwata
    Translational psychiatry, 11(1) 362-362, Jul 7, 2021  
    Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed "HLA-guided treatment schedule" and the "current schedule" being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the "HLA-guided treatment schedules," we considered a situation wherein the HLA test performed before clozapine initiation could provide "a priori information" by detecting patients harboring risk of HLA variants (HLA-B*59:01 and "HLA-B 158T/HLA-DQB1 126Q" for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% "prevention rate"). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of "HLA-guided treatment schedule" and "current schedule" used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the "HLA-guided treatment schedule" was more cost effective than the "current schedule"; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the "current schedule" of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.
  • Niamh Mullins, Andreas J Forstner, Kevin S O'Connell, Brandon Coombes, Jonathan R I Coleman, Zhen Qiao, Thomas D Als, Tim B Bigdeli, Sigrid Børte, Julien Bryois, Alexander W Charney, Ole Kristian Drange, Michael J Gandal, Saskia P Hagenaars, Masashi Ikeda, Nolan Kamitaki, Minsoo Kim, Kristi Krebs, Georgia Panagiotaropoulou, Brian M Schilder, Laura G Sloofman, Stacy Steinberg, Vassily Trubetskoy, Bendik S Winsvold, Hong-Hee Won, Liliya Abramova, Kristina Adorjan, Esben Agerbo, Mariam Al Eissa, Diego Albani, Ney Alliey-Rodriguez, Adebayo Anjorin, Verneri Antilla, Anastasia Antoniou, Swapnil Awasthi, Ji Hyun Baek, Marie Bækvad-Hansen, Nicholas Bass, Michael Bauer, Eva C Beins, Sarah E Bergen, Armin Birner, Carsten Bøcker Pedersen, Erlend Bøen, Marco P Boks, Rosa Bosch, Murielle Brum, Ben M Brumpton, Nathalie Brunkhorst-Kanaan, Monika Budde, Jonas Bybjerg-Grauholm, William Byerley, Murray Cairns, Miquel Casas, Pablo Cervantes, Toni-Kim Clarke, Cristiana Cruceanu, Alfredo Cuellar-Barboza, Julie Cunningham, David Curtis, Piotr M Czerski, Anders M Dale, Nina Dalkner, Friederike S David, Franziska Degenhardt, Srdjan Djurovic, Amanda L Dobbyn, Athanassios Douzenis, Torbjørn Elvsåshagen, Valentina Escott-Price, I Nicol Ferrier, Alessia Fiorentino, Tatiana M Foroud, Liz Forty, Josef Frank, Oleksandr Frei, Nelson B Freimer, Louise Frisén, Katrin Gade, Julie Garnham, Joel Gelernter, Marianne Giørtz Pedersen, Ian R Gizer, Scott D Gordon, Katherine Gordon-Smith, Tiffany A Greenwood, Jakob Grove, José Guzman-Parra, Kyooseob Ha, Magnus Haraldsson, Martin Hautzinger, Urs Heilbronner, Dennis Hellgren, Stefan Herms, Per Hoffmann, Peter A Holmans, Laura Huckins, Stéphane Jamain, Jessica S Johnson, Janos L Kalman, Yoichiro Kamatani, James L Kennedy, Sarah Kittel-Schneider, James A Knowles, Manolis Kogevinas, Maria Koromina, Thorsten M Kranz, Henry R Kranzler, Michiaki Kubo, Ralph Kupka, Steven A Kushner, Catharina Lavebratt, Jacob Lawrence, Markus Leber, Heon-Jeong Lee, Phil H Lee, Shawn E Levy, Catrin Lewis, Calwing Liao, Susanne Lucae, Martin Lundberg, Donald J MacIntyre, Sigurdur H Magnusson, Wolfgang Maier, Adam Maihofer, Dolores Malaspina, Eirini Maratou, Lina Martinsson, Manuel Mattheisen, Steven A McCarroll, Nathaniel W McGregor, Peter McGuffin, James D McKay, Helena Medeiros, Sarah E Medland, Vincent Millischer, Grant W Montgomery, Jennifer L Moran, Derek W Morris, Thomas W Mühleisen, Niamh O'Brien, Claire O'Donovan, Loes M Olde Loohuis, Lilijana Oruc, Sergi Papiol, Antonio F Pardiñas, Amy Perry, Andrea Pfennig, Evgenia Porichi, James B Potash, Digby Quested, Towfique Raj, Mark H Rapaport, J Raymond DePaulo, Eline J Regeer, John P Rice, Fabio Rivas, Margarita Rivera, Julian Roth, Panos Roussos, Douglas M Ruderfer, Cristina Sánchez-Mora, Eva C Schulte, Fanny Senner, Sally Sharp, Paul D Shilling, Engilbert Sigurdsson, Lea Sirignano, Claire Slaney, Olav B Smeland, Daniel J Smith, Janet L Sobell, Christine Søholm Hansen, Maria Soler Artigas, Anne T Spijker, Dan J Stein, John S Strauss, Beata Świątkowska, Chikashi Terao, Thorgeir E Thorgeirsson, Claudio Toma, Paul Tooney, Evangelia-Eirini Tsermpini, Marquis P Vawter, Helmut Vedder, James T R Walters, Stephanie H Witt, Simon Xi, Wei Xu, Jessica Mei Kay Yang, Allan H Young, Hannah Young, Peter P Zandi, Hang Zhou, Lea Zillich, Rolf Adolfsson, Ingrid Agartz, Martin Alda, Lars Alfredsson, Gulja Babadjanova, Lena Backlund, Bernhard T Baune, Frank Bellivier, Susanne Bengesser, Wade H Berrettini, Douglas H R Blackwood, Michael Boehnke, Anders D Børglum, Gerome Breen, Vaughan J Carr, Stanley Catts, Aiden Corvin, Nicholas Craddock, Udo Dannlowski, Dimitris Dikeos, Tõnu Esko, Bruno Etain, Panagiotis Ferentinos, Mark Frye, Janice M Fullerton, Micha Gawlik, Elliot S Gershon, Fernando S Goes, Melissa J Green, Maria Grigoroiu-Serbanescu, Joanna Hauser, Frans Henskens, Jan Hillert, Kyung Sue Hong, David M Hougaard, Christina M Hultman, Kristian Hveem, Nakao Iwata, Assen V Jablensky, Ian Jones, Lisa A Jones, René S Kahn, John R Kelsoe, George Kirov, Mikael Landén, Marion Leboyer, Cathryn M Lewis, Qingqin S Li, Jolanta Lissowska, Christine Lochner, Carmel Loughland, Nicholas G Martin, Carol A Mathews, Fermin Mayoral, Susan L McElroy, Andrew M McIntosh, Francis J McMahon, Ingrid Melle, Patricia Michie, Lili Milani, Philip B Mitchell, Gunnar Morken, Ole Mors, Preben Bo Mortensen, Bryan Mowry, Bertram Müller-Myhsok, Richard M Myers, Benjamin M Neale, Caroline M Nievergelt, Merete Nordentoft, Markus M Nöthen, Michael C O'Donovan, Ketil J Oedegaard, Tomas Olsson, Michael J Owen, Sara A Paciga, Chris Pantelis, Carlos Pato, Michele T Pato, George P Patrinos, Roy H Perlis, Danielle Posthuma, Josep Antoni Ramos-Quiroga, Andreas Reif, Eva Z Reininghaus, Marta Ribasés, Marcella Rietschel, Stephan Ripke, Guy A Rouleau, Takeo Saito, Ulrich Schall, Martin Schalling, Peter R Schofield, Thomas G Schulze, Laura J Scott, Rodney J Scott, Alessandro Serretti, Cynthia Shannon Weickert, Jordan W Smoller, Hreinn Stefansson, Kari Stefansson, Eystein Stordal, Fabian Streit, Patrick F Sullivan, Gustavo Turecki, Arne E Vaaler, Eduard Vieta, John B Vincent, Irwin D Waldman, Thomas W Weickert, Thomas Werge, Naomi R Wray, John-Anker Zwart, Joanna M Biernacka, John I Nurnberger, Sven Cichon, Howard J Edenberg, Eli A Stahl, Andrew McQuillin, Arianna Di Florio, Roel A Ophoff, Ole A Andreassen
    Nature genetics, 53(6) 817-829, Jun, 2021  
    Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.
  • Tempei Ikegame, Yosuke Hidaka, Yutaka Nakachi, Yui Murata, Risa Watanabe, Hiroko Sugawara, Tatsuro Asai, Emi Kiyota, Takeo Saito, Masashi Ikeda, Tsukasa Sasaki, Mamoru Hashimoto, Tomohisa Ishikawa, Minoru Takebayashi, Nakao Iwata, Chihiro Kakiuchi, Tadafumi Kato, Kiyoto Kasai, Miki Bundo, Kazuya Iwamoto
    Translational Psychiatry, 11(1), Jun, 2021  
    <title>Abstract</title><italic>SLC6A4</italic>, which encodes the serotonin transporter, has a functional polymorphism called the serotonin transporter-linked polymorphic region (5-HTTLPR). The 5-HTTLPR consists of short (S) and long (L) alleles, each of which has 14 or 16 tandem repeats. In addition, the extralong (XL) and other rare alleles have been reported in 5-HTTLPR. Although they are more frequent in Asian and African than in other populations, the extent of variations and allele frequencies (AFs) were not addressed in a large population. Here, we report the AFs of the rare alleles in a large number of Japanese subjects (<italic>N</italic> = 2894) consisting of two cohorts. The first cohort (case-control study set, CCSS) consisted of 1366 subjects, including 485 controls and 881 patients with psychosis (bipolar disorder or schizophrenia). The second cohort (the Arao cohort study set, ACSS) consisted of 1528 elderly subjects. During genotyping, we identified 11 novel 5-HTTLPR alleles, including 3 XL alleles. One novel allele had the longest subunit ever reported, consisting of 28 tandem repeats. We named this XL28-A. An in vitro luciferase assay revealed that XL28-A has no transcriptional activity. XL28-A was found in two unrelated patients with bipolar disorder in the CCSS and one healthy subject in the ACSS who did not show depressive symptoms or a decline in cognitive function. Therefore, it is unlikely that XL28-A is associated with psychiatric disorders, despite its apparent functional deficit. Our results suggest that unraveling the complex genetic variations of 5-HTTLPR will be important for further understanding its role in psychiatric disorders.
  • Takeo Saito, Masashi Ikeda, Shuji Hashimoto, Nakao Iwata
    Brain, behavior, and immunity, 94 471-471, May, 2021  
  • 谷口 賢, 齋藤 竹生, 池田 匡志, 岩田 仲生
    精神医学の基盤, 5(1) 137-144, Apr, 2021  
  • Koya Fukunaga, Ken Kato, Takuji Okusaka, Takeo Saito, Masashi Ikeda, Teruhiko Yoshida, Hitoshi Zembutsu, Nakao Iwata, Taisei Mushiroda
    Frontiers in Genetics, 12, Mar 18, 2021  
    Variability in the enzymatic activity of <italic>N</italic>-acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in <italic>N</italic>-acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated <italic>NAT2</italic> genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated <italic>in vitro</italic> kinetic parameters of four NAT2 alleles (NAT2∗4, ∗5, ∗6, and ∗7) for <italic>N</italic>-acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT2∗5, ∗6, and ∗7 exhibited significantly reduced <italic>N</italic>-acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT2∗4. Hierarchical clustering analysis revealed that 10 <italic>NAT2</italic> genotypes were categorized into three or four clusters. According to the results of <italic>in vitro</italic> metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05–54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
  • 二宮 光平, 齋藤 竹生, 池田 匡志, 岩田 仲生
    臨床精神薬理, 24(2) 145-149, Feb, 2021  
  • 齋藤 竹生, 池田 匡志, 岩田 仲生
    臨床精神薬理, 24(1) 13-20, Jan, 2021  
  • Masashi Ikeda, Takeo Saito, Tetsufumi Kanazawa, Nakao Iwata
    Journal of human genetics, 66(1) 53-60, Jan, 2021  
    Genome-wide association studies (GWASs) have detected many susceptible variants for common diseases, including psychiatric disorders. However, because of the small effect size of each variant, clinical utility that aims for risk prediction and/or diagnostic assistance based on the individual "variants" is difficult to use. Therefore, to improve the statistical power, polygenic risk score (PRS) has been established and applied in the GWAS as a robust analytic tool. Although PRS has potential predictive ability, because of its current "insufficient" discriminative power at the individual level for clinical use, it remains limited solely in the research area, specifically in the psychiatric field. For a better understanding of the PRS, in this review, we (1) introduce the clinical features of psychiatric disorders, (2) summarize the recent GWAS/PRS findings in the psychiatric disorders, (3) evaluate the problems of PRS, and (4) propose its possible utility to apply PRS into the psychiatric clinical setting.
  • Koya Fukunaga, Eiji Hishinuma, Masahiro Hiratsuka, Ken Kato, Takuji Okusaka, Takeo Saito, Masashi Ikeda, Teruhiko Yoshida, Hitoshi Zembutsu, Nakao Iwata, Taisei Mushiroda
    Journal of Human Genetics, Aug 5, 2020  Peer-reviewed
  • Tempei Ikegame, Miki Bundo, Naohiro Okada, Yui Murata, Shinsuke Koike, Hiroko Sugawara, Takeo Saito, Masashi Ikeda, Keiho Owada, Masaki Fukunaga, Fumio Yamashita, Daisuke Koshiyama, Tatsunobu Natsubori, Norichika Iwashiro, Tatsuro Asai, Akane Yoshikawa, Fumichika Nishimura, Yoshiya Kawamura, Jun Ishigooka, Chihiro Kakiuchi, Tsukasa Sasaki, Osamu Abe, Ryota Hashimoto, Nakao Iwata, Hidenori Yamasue, Tadafumi Kato, Kiyoto Kasai, Kazuya Iwamoto
    Schizophrenia Bulletin, Jun 19, 2020  Peer-reviewed
    <title>Abstract</title> Associations between altered DNA methylation of the serotonin transporter (5-HTT)-encoding gene SLC6A4 and early life adversity, mood and anxiety disorders, and amygdala reactivity have been reported. However, few studies have examined epigenetic alterations of SLC6A4 in schizophrenia (SZ). We examined CpG sites of SLC6A4, whose DNA methylation levels have been reported to be altered in bipolar disorder, using 3 independent cohorts of patients with SZ and age-matched controls. We found significant hypermethylation of a CpG site in SLC6A4 in male patients with SZ in all 3 cohorts. We showed that chronic administration of risperidone did not affect the DNA methylation status at this CpG site using common marmosets, and that in vitro DNA methylation at this CpG site diminished the promoter activity of SLC6A4. We then genotyped the 5-HTT-linked polymorphic region (5-HTTLPR) and investigated the relationship among 5-HTTLPR, DNA methylation, and amygdala volume using brain imaging data. We found that patients harboring low-activity 5-HTTLPR alleles showed hypermethylation and they showed a negative correlation between DNA methylation levels and left amygdala volumes. These results suggest that hypermethylation of the CpG site in SLC6A4 is involved in the pathophysiology of SZ, especially in male patients harboring low-activity 5-HTTLPR alleles.
  • Saito T, Ikeda M, Mushiroda T, Iwata N, Clozapine Pharmacogenomics Consortium of Japan
    Aust N Z J Psychiatry, 54(5) 545-546, May, 2020  Peer-reviewed
  • 池田 匡志, 斎藤 竹生, 大河内 智, 岩田 仲生
    実験医学, 38(4) 556-559, Mar, 2020  
  • Kosei Esaki, Masashi Ikeda, Tomo Okochi, Satoru Taniguchi, Kohei Ninomiya, Ayu Shimasaki, Yasuyo Otsuka, Yoshiko Oda, Takaya Sakusabe, Keiko Mano, Takeo Saito, Nakao Iwata
    PloS one, 15(10) e0240466, 2020  
    Depressive symptoms are a serious problem in workplaces. Hospital staff members, such as newly licensed registered nurses (NLRNs), are at particularly increased risk of these symptoms owing to their limited experience. Previous studies have shown that a brief program-based cognitive behavioral therapy program (CBP) can offer effective treatment. Here, we conducted a longitudinal observational study of 683 NLRNs (CBP group, n = 522; no-CBP group, n = 181) over a period of 1 year (six times surveys were done during this period). Outcomes were assessed on the basis of surveys that covered the Beck Depression Inventory-I (BDI). The independent variables were CBP attendance (CBP was conducted 3 months after starting work), personality traits, personal stressful life events, workplace adversity, and pre-CBP change in BDI in the 3 months before CBP (ΔBDIpre-CBP). All factors were included in Cox proportional hazards models with time-dependent covariates for depressive symptoms (BDI ≥10), and we reported hazard ratios (HRs). Based on this analysis, we detected that CBP was significantly associated with benefit for depressive symptoms in all NLRNs (Puncorrected = 0.0137, HR = 0.902). To identify who benefitted most from CBP, we conducted a subgroup analysis based on the change in BDI before CBP (ΔBDIpre-CBP). The strongest association was when BDI scores were low after starting work and increased before CBP (Puncorrected = 0.00627, HR = 0.616). These results are consistent with previous findings, and indicate that CBP may benefit the mental health of NLRNs. Furthermore, selective prevention based on the pattern of BDI change over time may be important in identifying who should be offered CBP first. Although CBP is generally effective for all nurses, such a selective approach may be most appropriate where cost-effectiveness is a prominent concern.
  • Murata Y, Ikegame T, Koike S, Saito T, Ikeda M, Sasaki T, Iwata N, Kasai K, Bundo M, Iwamoto K
    Prog Neuropsychopharmacol Biol Psychiatry, 99 109855-109855, Jan, 2020  Peer-reviewed
    Accumulating evidence suggests that aberrant epigenetic regulation is involved in the pathophysiology of major psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD). We previously showed that the plasma level of betaine (N,N,N-trimethylglycine), a methyl-group donor, was significantly decreased in patients with first episode schizophrenia (FESZ). In this study, we identified decrease of global DNA methylation level in FESZ (N = 24 patients vs N = 42 controls), and found that global DNA methylation level was inversely correlated with scores on the global assessment of functioning (GAF) scale, and positively correlated with plasma betaine level. Notably, correlations between levels of betaine and its metabolites (N,N-dimethylglycine and sarcosine, N-methylglycine) were lower or lost in FESZ plasma, but remained high in controls. We further examined global DNA methylation levels in patients with chronic SZ (N = 388) and BD (N = 414) as well as controls (N = 430), and confirmed significant hypomethylation and decreased betaine level in SZ. We also found that patients with BD type I, but not those with BD type II, showed significant global hypomethylation. These results suggest that global hypomethylation associated with decreased betaine level in blood cells is common to SZ and BD, and may reflect common pathophysiology such as psychotic symptoms.
  • Taniguchi S, Ninomiya K, Kushima I, Saito T, Shimasaki A, Sakusabe T, Momozawa Y, Kubo M, Kamatani Y, Ozaki N, Ikeda M, Iwata N
    Psychiatry and clinical neurosciences, 74(1) 35-39, Aug, 2019  Peer-reviewed
  • Masashi Ikeda, Atsushi Takahashi, Yoichiro Kamatani, Yukihide Momozawa, Takeo Saito, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Takaya Sakusabe, Yoshimi Iwayama, Tomoko Toyota, Tomoyasu Wakuda, Mitsuru Kikuchi, Nobuhisa Kanahara, Hidenaga Yamamori, Yuka Yasuda, Yuichiro Watanabe, Satoshi Hoya, Branko Aleksic, Itaru Kushima, Heii Arai, Manabu Takaki, Kotaro Hattori, Hiroshi Kunugi, Yuko Okahisa, Tohru Ohnuma, Norio Ozaki, Toshiyuki Someya, Ryota Hashimoto, Takeo Yoshikawa, Michiaki Kubo, Nakao Iwata
    Schizophrenia bulletin, 45(4) 824-834, Jun 18, 2019  Peer-reviewed
    Genome-wide association studies (GWASs) have identified >100 susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian [EAS] and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD]) within EAS and between EAS and EUR (trans-diseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (Pbest = 4.1 × 10-10), SLC38A3 (Pbest = 5.7 × 10-10), and CABP1-ACADS (Pbest = 9.8 × 10-9). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (Pbest = 4.0 × 10-11) and between SCZ and BD in the JPN population (P ~ 10-40); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was ρ = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, rg = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, ρ = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.
  • Masashi Ikeda, Satoshi Tanaka, Takeo Saito, Norio Ozaki, Yoichiro Kamatani, Nakao Iwata
    Psychological Medicine, 48(10) 1745-1748, Jul 1, 2018  Peer-reviewed
  • Hiroko Sugawara, Yui Murata, Tempei Ikegame, Rie Sawamura, Shota Shimanaga, Yusuke Takeoka, Takeo Saito, Masashi Ikeda, Akane Yoshikawa, Fumichika Nishimura, Yoshiya Kawamura, Chihiro Kakiuchi, Tsukasa Sasaki, Nakao Iwata, Mamoru Hashimoto, Kiyoto Kasai, Tadafumi Kato, Miki Bundo, Kazuya Iwamoto
    Psychiatry and clinical neurosciences, 72(4) 245-254, Apr, 2018  Peer-reviewed
    AIM: Schizophrenia (SZ) and bipolar disorder (BD) have been known to share genetic and environmental risk factors, and complex gene-environmental interactions may contribute to their pathophysiology. In contrast to high genetic overlap between SZ and BD, as revealed by genome-wide association studies, the extent of epigenetic overlap remains largely unknown. In the present study, we explored whether SZ and BD share epigenetic risk factors in the same manner as they share genetic components. METHODS: We performed DNA methylation analyses of the CpG sites in the top five candidate regions (FAM63B, ARHGAP26, CTAGE11P, TBC1D22A, and intergenic region [IR] on chromosome 16) reported in a previous methylome-wide association study (MWAS) of SZ, using whole blood samples from subjects with BD and controls. RESULTS: Among the five candidate regions, the CpG sites in FAM63B and IR on chromosome 16 were significantly hypomethylated in the samples from subjects with BD as well as those from subjects with SZ. On the other hand, the CpG sites in TBC1D22A were hypermethylated in the samples from subjects with BD, in contrast to hypomethylation in the samples from subjects with SZ. CONCLUSION: Hypomethylation of FAM63B and IR on chromosome 16 could be common epigenetic risk factors for SZ and BD. Further comprehensive epigenetic studies for BD, such as MWAS, will uncover the extent of similarity and uniqueness of epigenetic alterations.
  • M Ikeda, A Takahashi, Y Kamatani, Y Okahisa, H Kunugi, N Mori, T Sasaki, T Ohmori, Y Okamoto, H Kawasaki, S Shimodera, T Kato, H Yoneda, R Yoshimura, M Iyo, K Matsuda, M Akiyama, K Ashikawa, K Kashiwase, K Tokunaga, K Kondo, T Saito, A Shimasaki, K Kawase, T Kitajima, K Matsuo, M Itokawa, T Someya, T Inada, R Hashimoto, T Inoue, K Akiyama, H Tanii, H Arai, S Kanba, N Ozaki, I Kusumi, T Yoshikawa, M Kubo, N Iwata
    Molecular psychiatry, 23(3) 639-647, Mar, 2018  
    Genome-wide association studies (GWASs) have identified several susceptibility loci for bipolar disorder (BD) and shown that the genetic architecture of BD can be explained by polygenicity, with numerous variants contributing to BD. In the present GWAS (Phase I/II), which included 2964 BD and 61 887 control subjects from the Japanese population, we detected a novel susceptibility locus at 11q12.2 (rs28456, P=6.4 × 10-9), a region known to contain regulatory genes for plasma lipid levels (FADS1/2/3). A subsequent meta-analysis of Phase I/II and the Psychiatric GWAS Consortium for BD (PGC-BD) identified another novel BD gene, NFIX (Pbest=5.8 × 10-10), and supported three regions previously implicated in BD susceptibility: MAD1L1 (Pbest=1.9 × 10-9), TRANK1 (Pbest=2.1 × 10-9) and ODZ4 (Pbest=3.3 × 10-9). Polygenicity of BD within Japanese and trans-European-Japanese populations was assessed with risk profile score analysis. We detected higher scores in BD cases both within (Phase I/II) and across populations (Phase I/II and PGC-BD). These were defined by (1) Phase II as discovery and Phase I as target, or vice versa (for 'within Japanese comparisons', Pbest~10-29, R2~2%), and (2) European PGC-BD as discovery and Japanese BD (Phase I/II) as target (for 'trans-European-Japanese comparison,' Pbest~10-13, R2~0.27%). This 'trans population' effect was supported by estimation of the genetic correlation using the effect size based on each population (liability estimates~0.7). These results indicate that (1) two novel and three previously implicated loci are significantly associated with BD and that (2) BD 'risk' effect are shared between Japanese and European populations.
  • Masashi Ikeda, Takeo Saito, Kenji Kondo, Nakao Iwata
    Psychiatry and Clinical Neurosciences, 72(2) 52-63, Feb 1, 2018  Peer-reviewed
  • Takeo Saito, Masashi Ikeda, Ryota Hashimoto, Nakao Iwata, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Masami Miyata, Taisei Mushiroda, Takeshi Ozeki, Michiaki Kubo, Kiyoshi Fujita, Naoya Kida, Minori Nakai, Taku Otsuru, Yasuhide Fukuji, Masaru Murakami, Kentaro Mizuno, Toshiaki Shiratsuchi, Shusuke Numata, Tetsuro Ohmori, Shu-Ichi Ueno, Yuji Yada, Sadakazu Tanaka, Yoshiki Kishi, Manabu Takaki, Akiko Mamoto, Norio Taniguchi, Yutaka Sawa, Haruo Watanabe, Tetsuro Noda, Yuuhei Amano, Takemi Kimura, Taku Fukao, Taro Suwa, Toshiya Murai, Masaharu Kubota, Keishi Ueda, Hideaki Tabuse, Nobuhisa Kanahara, Nobutoshi Kawai, Kiyotaka Nemoto, Manabu Makinodan, Yosuke Nishihata, Naoki Hashimoto, Ichiro Kusumi, Yasuo Fujii, Ryoji Miyata, Kyuryoku Hirakawa, Norio Ozaki
    Biological psychiatry, 82(1) e9-e10-e10, Jul 1, 2017  Peer-reviewed
  • Naruhisa Yamaki, Akitoyo Hishimoto, Ikuo Otsuka, Toru Sasada, Shuken Boku, Takeo Saito, Yuka Yasuda, Hidenaga Yamamori, Masashi Ikeda, Manabu Ikeda, Ichiro Sora, Nakao Iwata, Ryota Hashimoto
    PSYCHIATRY AND CLINICAL NEUROSCIENCES, 71(4) 289-290, Apr, 2017  Peer-reviewed
  • Kohei Kawase, Kenji Kondo, Takeo Saito, Ayu Shimasaki, Atsushi Takahashi, Yoichiro Kamatani, Naoto Kawabe, Senju Hashimoto, Masashi Ikeda, Michiaki Kubo, Kentaro Yoshioka, Nakao Iwata
    PSYCHIATRY AND CLINICAL NEUROSCIENCES, 70(11) 489-497, Nov, 2016  Peer-reviewed
  • Takeo Saito, Masashi Ikeda, Taisei Mushiroda, Takeshi Ozeki, Kenji Kondo, Ayu Shimasaki, Kohei Kawase, Shuji Hashimoto, Hidenaga Yamamori, Yuka Yasuda, Michiko Fujimoto, Kazutaka Ohi, Masatoshi Takeda, Yoichiro Kamatani, Shusuke Numata, Tetsuro Ohmori, Shu-ichi Ueno, Manabu Makinodan, Yosuke Nishihata, Masaharu Kubota, Takemi Kimura, Nobuhisa Kanahara, Naoki Hashimoto, Kiyoshi Fujita, Kiyotaka Nemoto, Taku Fukao, Taro Suwa, Tetsuro Noda, Yuji Yada, Manabu Takaki, Naoya Kida, Taku Otsuru, Masaru Murakami, Atsushi Takahashi, Michiaki Kubo, Ryota Hashimoto, Nakao Iwata
    BIOLOGICAL PSYCHIATRY, 80(8) 636-642, Oct, 2016  Peer-reviewed
  • Jun Egawa, Satoshi Hoya, Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Emiko Inoue, Shujiro Okuda, Kenji Kondo, Takeo Saito, Naoshi Kaneko, Tatsuyuki Muratake, Hirofumi Igeta, Nakao Iwata, Toshiyuki Someya
    AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS, 171(6) 797-805, Sep, 2016  Peer-reviewed
  • Yuichiro Watanabe, Ayako Nunokawa, Masako Shibuya, Masashi Ikeda, Akitoyo Hishimoto, Kenji Kondo, Jun Egawa, Naoshi Kaneko, Tatsuyuki Muratake, Takeo Saito, Satoshi Okazaki, Ayu Shimasaki, Hirofumi Igeta, Emiko Inoue, Satoshi Hoya, Takuro Sugai, Ichiro Sora, Nakao Iwata, Toshiyuki Someya
    PSYCHIATRY RESEARCH, 235 13-18, Jan, 2016  Peer-reviewed
  • Masashi Ikeda, Ayu Shimasaki, Atsushi Takahashi, Kenji Kondo, Takeo Saito, Kohei Kawase, Kosei Esaki, Yasuyo Otsuka, Keiko Mano, Michiaki Kubo, Nakao Iwata
    JOURNAL OF CLINICAL PSYCHIATRY, 77(1) E29-+, Jan, 2016  Peer-reviewed
  • Masakazu Hatano, Masashi Ikeda, Kenji Kondo, Takeo Saito, Ayu Shimasaki, Kosei Esaki, Wakako Umene-Nakano, Reiji Yoshimura, Jun Nakamura, Norio Ozaki, Nakao Iwata
    JOURNAL OF HUMAN GENETICS, 60(6) 343-344, Jun, 2015  Peer-reviewed
  • Masashi Ikeda, Reiji Yoshimura, Ryota Hashimoto, Kenji Kondo, Takeo Saito, Ayu Shimasaki, Kazutaka Ohi, Mamoru Tochigi, Yoshiya Kawamura, Nao Nishida, Taku Miyagawa, Tsukasa Sasaki, Katsushi Tokunaga, Kiyoto Kasai, Masatoshi Takeda, Jun Nakamura, Norio Ozaki, Nakao Iwata
    JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 35(1) 85-88, Feb, 2015  Peer-reviewed

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